The amide bond is a key functional group in organic chemistry. It plays a major role in the elaboration and composition of biological and chemical systems. Amides are typically synthesized by coupling of activated carboxylic acid derivatives with amines. Alternative strategies toward the synthesis of amides are the Staudinger reaction [Saxon, E, & Bertozzi, C R, Science (2000) 287, 2007; Damkaci, F, & DeShong, P, J. Am. Chem. Soc. (2003) 125, 4408; Gololobov, Y G, & Kasukhin, L F, Tetrahedron (1992) 48, 1353; Pianowski, Z, et al., J. Am. Chem. Soc. (2009) 131, 6492], the Schmidt reaction [Ribelin, T, et al., Angew. Chem. Int. Ed. (2008) 47, 6233; Lang, S, & Murphy, J A, Chem. Soc. Rev. (2006) 35, 146], Beckmann rearrangement [Owston, N A, et al., Org. Lett. (2007) 9, 3599; Hashimoto, M, et al., J. Org. Chem. (2008) 73, 2894], aminocarbonylation of haloarenes [Martinelli, J R, et al., Angew. Chem. Int. Ed. (2007) 46, 8460; Nanayakkara, P & Alper, H, Chem. Commun. (2003) 2384], alkenes [Beller, M, et al., J. Mol. Catal. A: Chem. (1995) 104, 17] and alkynes [Ali, B E, & Tijani, J, Appl. Organomet. Chem. (2003) 17, 921; Knapton, D J, & Meyer, T Y, Org. Lett. (2004) 6, 687; Uenoyama, Y, et al., Angew Chem. Int. Ed. (2005) 44, 1075; Park, J H, et al., Org. Lett. (2007) 9, 2465], oxidative amidation of aldehydes [Chang, J W W, & Chan, P W H, Angew Chem. Int. Ed. (2008) 47, 1138; Yoo, W J, & Li, C J, J. Am. Chem. Soc. (2006) 128, 13064; Tillack, A, et al., Eur. J. Org. Chem. (2001) 523; Naota, T, & Murahashi, S-I, Synlett (1991) 693], hydrative amide synthesis with alkynes [Cho, S, et al., J. Am. Chem. Soc. (2005) 127, 16046] and the amidation of thioacids with azides [Kolakowski, R V, et al., J. Am. Chem. Soc. (2006) 128, 5695; Zhang, X, et al., Bioconjugate Chem. (2009) 20, 197]. However, most of these methods require equimolar amounts of various reagents and generate tantamount of byproducts as waste with tedious procedures. Therefore, synthesis of amides under neutral conditions and without the generation of waste is a challenging goal.
Recently, the Milstein group reported an environmentally friendly direct amidation of alcohols and amines with liberating two molecules of hydrogen using a ruthenium PNN pincer, complex without any base or acid promoters [US patent application 2009/0112005; Gunanathan, C, et al., Science (2007) 317, 790]. This Milstein catalyst has been commercialized through Strem Chemicals, Inc (Newburyport, Mass.). Since then, several groups have reported the amide synthesis from alcohols and amines using ruthenium [Watson, A J A, et al, Org. Lett. (2009) 11, 2667; Nordstrøm, L U, et al., J. Am. Chem. Soc. (2008) 130, 17672] and rhodium [Zweifel, T, et al., Angew. Chem. Int. Ed. (2009) 48, 559] catalysts. Particularly, the Madsen group showed that Ru(COD)Cl2 with an N-heterocyclic carbene (NHC) and phosphine ligands also catalyzed the formation of an amide rather than the alkylation of an amine. The direct acylation of amines with alcohols is a highly atom economical transformation with hydrogen as a sole byproduct and less waste than traditional amide synthesis. A drawback of such methods of amide production using phosphines is the high toxicity of these compounds, a concentration of 2.8 mg phosphine per liter air being lethal. Further, tertiary phosphines are often air sensitive and are subject to P—C bond degradation at elevated temperatures. In addition, phosphines are expensive. Hence, there remains a need for a further process of forming amides.
It is accordingly an object of the present invention to provide a process that is suitable for the production of amides and that avoids at least some of the above named draw-backs in current processes of amide production. This object is solved by the method of claim 1.